This MDRC renewal brings together talented new and experienced investigators, unique resources, and innovative techniques to develop medications for the treatment of cocaine, heroin and other opioids, and marijuana abuse. Each of these needs new or improved medications for effective treatment. The current MDRC has as its major themes the development of effective medications for subgroups of the addict population, the search for better methods to identify them, and the development and evaluation of medications for emerging problems. The renewal consists of two Cores and five Projects, among which there is considerable interaction. The Clinical Core, in addition to centralized recruiting, coordination, support and provision of basic psychosocial therapy, will carry out placebo-controlled pilot studies on promising new medications, and supports inpatient and outpatient research facilities for pilots and projects. The pilot projects continue to be successful, and have resulted in independent funding. The Biostatistical, Training, and Education Core provides statistical support from design to analysis, and extensive education (with our Fellowship program) to medical students, residents, and fellows. Project 1 uses the heroin self-administration model developed in the initial MDRC to evaluate prescription opioids, alone and in combination with buprenorphine. Project 2 combines innovative imaging of the D1 and kappa opioid receptors (KOR) with our model of cocaine self-administration to investigate whether the D1 and KOR receptor availabilities will be predictive of vulnerability to cocaine-induced cocaine-seeking. Project 3, using the targeted subgroup model and innovative design features, will use an abstinence-induction method to further assess the efficacy of venlafaxine in cocaine abusers with primary depression. Project 4 (based on laboratory data from Project 5 and a Center-funded pilot study) proposes a clinical trial to determine if dronabinol will reduce marijuana withdrawal symptoms and improve marijuana abstinence in marijuana-dependent individuals. Project 5 proposes to develop a model of marijuana relapse in order to study the effects of potential treatment medications (oral THC, nefazodone, the cannabinoid receptor antagonist SR 141716) with marijuana abusers, evaluating agents that may either ameliorate marijuana abstinence symptoms or reduce marijuana's acute effects. Overall, the Center has the potential to develop better medications and models for treating abuse of these three drugs, and, to meet this goal, has the unique ability to rapidly move back and forth between human laboratory and clinical studies. It works closely with the NIDA CTN project, locally and nationally, contributing both ideas and clinical researchers.